DESCRIPTION (Adapted from applicant?s abstract): Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disorder associated with severe loss of motor neurons in the brain, brainstem and spinal cord. ALS typically has a rapid course and leads to death within 3 to 5 years after the onset of clinical symptoms. Approximately 10 percent of cases are thought to have a genetic basis and are referred to as "familial ALS." One form of familial ALS (ALS1) maps to chromosome 21q22 and is associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene. While ALS is a type is a disorder that is almost exclusively seen in adults, there are forms of ALS that have onset in childhood or adolescence, and manifest a chronic, slowly progressive course. This type of ALS is termed "juvenile ALS." We identified a region on chromosome 9q34 which harbors the gene for an autosomal dominant form of juvenile ALS. The various forms of ALS and juvenile ALS are devastating neurological disorders lacking a defined pathophysiological basis and any effective therapies. The purpose of this application is to identify and characterize the gene for juvenile ALS mapping to chromosome 9q34, also known as the ALS4 locus. Specific Aim (1) is to search for mutations in known candidate genes mapping within the ALS4 candidate region on chromosome 9q34 in order to identify the gene for ALS4. Specific Aim (2) is to search for additional transcripts as candidate genes for ALS4 by direct cDNA selection and other positional cloning methods, if our evaluation of the known candidate genes from the critical region fails to yield the causal gene. Specific Aim (3) is to characterize the genomic structure of the ALS4 gene by standard molecular genetic approaches and to determine the expression pattern of the ALS4 gene and the ALS protein by nucleic acid hybridization and immunohistochemical methods using specific probes and/or antibodies. Specific Aim (4) is to identify the functional domains of the ALS gene by sequence-similarity comparisons and analysis of homologous and orthologous genes from other species and by biochemical analysis. Specific Aim (5) is to develop an animal model of ALS4 by introducing an identified disease-causing mutation into the germline of the mouse by employing either transgenesis or gene targeting.